Auswahl der wissenschaftlichen Literatur zum Thema „Substitut de thorax humain“

A major paradox of modern happiness gained wide public exposure in 1776 when Thomas Jefferson substituted the phrase “the pursuit of happiness” in place of Locke’s formulation: “life, liberty, and property.” In substituting happiness for property, Jefferson obscured the central hypocrisy of the Revolution, that—as contemporaries complained—the “loudest yelps for liberty” were made by those practicing slavery. Jefferson elided the overlap between the pursuit of happiness and the protection of human property. And he blurred the connection between the assertion of slave power and the creation of a broad emotional hegemony in the service of multifaceted projects of political-economic mastery. Today, historians of emotion face an urgent need to explore the deep roots of this feeling in systems of unfreedom.

Lights are essential for humans and other living creatures. Without lights or lighting, surely it will be hard to do everything, especially in the afternoon or at night. As the development of civilization and technology, humans created artificial lighting. For the first time, it was only a substitute for natural light from the sun. Artificial light was provided from the fire; then research and development of the light bulb were conducted by Alessandro Volta, Sir Humphry Davy, Warren De La Rue, to Thomas Alva Edison. After the natural lights from the sun can be replaced by artificial lighting from the lamp, the development of lighting is getting much complex ranging from technical to psychological things. This relates to the increasing human activity in the room. The diversity of different activity requires different types of lighting methods. The development results not only about technical and psychological problems but also aesthetic elements.

Polar VOCs represented by ketones deteriorate indoor air quality and affect human health. Adsorption by activated carbons can effectively remove harmful gases, but relatively little is known about the adsorption capacity of polar VOCs at a low concentration level. So, this paper adopted acetone as the typical polar VOC to test its adsorption on the coconut shell activated carbon and developed a prediction model to estimate the breakthrough time. The results will help users master the acetone adsorption behavior under realistic conditions and thus estimate the service life of the filters. The adsorption test of acetone with concentrations of 0.5, 1.0, 2.0, 3.0, and 4.0 ppm was carried out. Four adsorption isotherms, namely, Langmuir, Freundlich, Dubinin–Radushkevich, and Temkin, were used to fit the data. The Freundlich model fitted best when was used to determine the equilibrium capacity of acetone. An approach based on the Thomas model was proposed to predict the acetone breakthrough curve. The mass transfer coefficient of acetone adsorption with a relatively high concentration (1.0–4.0 ppm) was calculated based on the Thomas model, and the relationship between the mass transfer coefficient and acetone inlet concentration was established to obtain the mass transfer coefficient of acetone at the predicted concentration. The equilibrium capacity and mass transfer coefficient were substituted into the Thomas model to predict the breakthrough curve of acetone at a lower concentration. The results showed that the shape of the predicted curve was much closer to the measured data of acetone adsorption. The relative deviation between the predicted service life and measured data was 10%, indicating that the Thomas model was suitable for predicting acetone adsorption at low concentrations.

Technological developments have created many innovations that help make human life more manageable. One of these developments is the Bariska Robot presented at the Family Mart Grand Indonesia Store, Jakarta. Even though its existence is welcomed, quite a few feel that it is a threat to humans because it is considered that it can replace the role of the Barista. The presence of robot baristas cannot replace the baristas themselves. Baristas have values ​​that apparently cannot be imitated by robots. In this research, the author used the library research method to collect information according to the needs of this research. As well as using Thomas S. Kuhn's ideas to examine the role of paradigms in the scientific revolution. Which is the basis of the technological changes that occur.

Abstract Drug combinations targeting the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR) have been used to treat EGFR-expressing cancers. In addition, we observed that the combination of the EGFR inhibitor erlotinib and the VEGFR2 inhibitor cediranib had greater activity in patient-derived xenografts (PDX) from rare cancers compared to the single agents alone. To better understand the combination activity and seek potential alternatives for each drug, their inhibition of 370 wild type human kinases was measured with a biochemical enzymatic assay. The single agents and combinations were tested at the IC50 value for their primary targets, 500 nM as a common reference concentration, and Cmax as achievable clinical concentrations. At the clinical Cmax, cediranib (148 nM) inhibited 5 kinases, including VEGFR2, by >90% and inhibited EGFR by 75%. Erlotinib (clinical Cmax 3.15 µM) inhibited 9 kinases, including EGFR, by ≥89% and inhibited VEGFR2 by 82%. When combined at their clinical concentrations (Cmax), cediranib + erlotinib inhibited 18 kinases by ≥89%. Kinase inhibition profiles were measured for 7 agents that were candidate alternatives for cediranib or erlotinib, including: vandetanib, erdafitinib, axitinib, lenvatinib, cabozantinib, poziotinib, and mobocertinib (note: Cmax values varied 58-fold among the drugs). At clinical Cmax, cediranib showed the greatest similarity to axitinib and lenvatinib based on their kinase inhibition profiles, whereas erlotinib showed the greatest similarity to poziotinib and vandetanib. The rank order of drug similarities based on biochemical kinase inhibition profiles aligned with the NCI-60 cell-based activities of the drugs according to a COMPARE Analysis. The Bliss independence model was used to calculate the combination activity of cediranib + erlotinib from single agent data for comparison with the experimental results of the drug combination. The high correlation between the calculated and experimental datasets indicated that the model could be used to assess other drug combinations from single agent data. Comparisons of the calculated kinase inhibition profiles of the novel drug combinations to the profile of cediranib + erlotinib indicated that erlotinib would be difficult to replace; however, cediranib might be substituted by either lenvatinib or axitinib. Similarities in the activities of erlotinib in combination with cediranib, lenvatinib and axitinib were observed in complex spheroids containing patient-derived cells as well as PDX models. These results suggest that the additive effect of VEGFR inhibition on erlotinib activity may not solely be due to erlotinib’s EGFR inhibitory activity, and therefore may not be seen with other EGFR inhibitors. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: Nathan P. Coussens, Thomas S. Dexheimer, Thomas Silvers, Shannon Uzelac, Kyle Georgius, John Carter, Tia Shearer, Rekha Rao, Karen Gray, Apurva K. Srivastava, Robert J. Kinders, Yvonne A. Evrard, Melinda G. Hollingshead, Joel Morris, Jeffrey A. Moscow, Ralph E. Parchment, Beverly A. Teicher, James H. Doroshow. Biochemical inhibition profiles of 370 wild type human kinases provide a basis for selecting alternative combinations of EGFR and VEGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2665.

Abstract Adoptive T cell therapy (ACT) has demonstrated activity in solid tumors but requires further optimization to become a reproducibly effective treatment. T cell receptor (TCR)-engineered T cells recognize peptides derived from intracellular and surface proteins presented in the context of MHC class I. Targeting mutated oncogenic drivers addresses some of the major obstacles of this modality, in that the antigenic epitope is: 1) tumor-specific, 2) essential for tumor survival, and 3) derived from a stably expressed protein. KRAS is the most frequently mutated gene in human cancers with alterations in codon 12 associated with poor clinical outcomes in a high proportion of colon, lung and pancreatic cancers, as well as many others. To isolate TCRs specific for the peptide derived from the KRAS G12D mutation presented in the context of HLA-A*11:01, one of the most common HLA alleles worldwide, we employed our high-throughput in vitro TCR discovery platform. CD8+ T cells were isolated from healthy donors and co-cultured with autologous antigen-presenting cells exogenously-loaded with mutant KRAS peptides encompassing the G12D mutation. The highest avidity T cells were subsequently identified and enriched by fluorescence-based cell sorting and the corresponding TCR genes isolated by single-cell sequencing and inserted into a lentiviral expression vector. TCR candidates were transduced into primary T cells and prioritized based on functional avidity and specificity (response to titrated peptide-loaded presenting cells and tumor cells endogenously expressing the KRAS G12D antigen) and cytotoxicity (in vitro tumor cell killing assays). X-Scan studies, in which each residue of the reference KRAS G12D peptide was systematically substituted by all other amino acids, revealed a highly restrictive TCR recognition motif, suggesting limited risk of promiscuous off-target activation. We engineered both CD4+ and CD8+ T cells to lentivirally-express candidate TCRs in addition to the genes encoding the CD8αβ co-receptor to enhance TCR-HLA class I avidity in CD4+ T cells, with the aim of creating a coordinated CD4 and CD8 T cell response to the same tumor target to promote increased T cell activity and persistence while minimizing T cell exhaustion. Transduced CD4+ T cells were functional and could be demonstrated to provide help to CD8+ T cells, supporting tumor elimination in several experimental models. In summary, we report a TCR gene therapy approach targeting mutant KRAS G12D-containing peptides with a coordinated CD4 and CD8 T cell response that has a promising efficacy and safety profile. Our work to date supports the planned clinical development of this novel TCR-engineered T cell therapy for treating KRAS-mutant solid tumors. Citation Format: Cheryl Black, James Parsons, Anthony Thomas, Allison P. Drain, Santosh Narayan, Joshua Francis, Xingyue He, Ankit Gupta, Jessica Webb, Thomas M. Schmitt, Philip D. Greenberg, Gary Shapiro, Loïc Vincent. Preclinical development of safe and effective T cell receptors specific for mutant KRAS G12D peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1127.

SCIENCE, RELIGION, AND THE PROTESTANT TRADITION: Retracing the Origins of Conflict by James C. Ungureanu. Pittsburgh, PA: University of Pittsburgh Press, 2019. x + 358 pages. Hardcover; $50.00. ISBN: 9780822945819. *Mythical understandings about historical intersections of Christianity and science have a long history, and persist in our own day. Two American writers are usually cited as the architects of the mythology of inevitable warfare between science and religion: John William Draper (1811-1882) and Andrew Dickson White (1832-1919). Draper was a medical doctor, chemist, and historian. White was an academic (like Draper), a professional historian, and first president of the nonsectarian Cornell University. Ungureanu's objective is to show how Draper and White have been (mis)interpreted and (mis)used by secular critics of Christianity, liberal theists, and historians alike. *Ungureanu opens by critiquing conflict historians as misreading White and Draper. The conflict narrative emerged from arguments within Protestantism from the sixteenth through nineteenth centuries, and, as taken up by Draper and White, was intended not to annihilate religion but to reconcile religion with science. Consequently, the two were not the anti-religious originators of science-versus-religion historiography. Rather, the "warfare thesis" began among sixteenth- and seventeenth-century Protestant historians and theologians attacking both Roman Catholics and each other. By the early nineteenth century, the purpose of conflict polemics was not to crush religion in the name of science but to clear intellectual space for preserving a "purified" and "rational" religion reconciled to science. Widespread beliefs held by liberal Protestant men of science included "progressive" development or evolution in history and nature as found, for example, in books by Lamarck in France and Robert Chambers in Britain. For Draper, English chemist and Unitarian minister Joseph Priestley (1733-1804) was a model of faith without the burden of orthodoxy. *So conflict rhetoric arose not, as we've been taught before, in post-Darwinian controversies, but in contending narratives within generations of earlier Protestant reformers who substituted personal judgment for ecclesial authority. Victorian scientific naturalists and popularizers often rejected Christian theological beliefs in the name of a "natural" undogmatic "religion" (which could slip into varieties of Unitarianism, deism, agnosticism, or pantheism). In effect, the conflict was not between science and religion, but between orthodox Christian faith and progressive or heterodox Christian faith--a conflict between how each saw the relationship between Christian faith and science. Draper, White, and their allies still saw themselves as theists, even Protestant Christians, though as liberal theists calling for a "New Reformation." Given past and present anti-Christian interpretations of these conflict historians with actual religious aims, this is ironic to say the least. *Ungureanu's thesis shouldn't be surprising. In the Introduction to his History of the Warfare, White had written: "My conviction is that Science, though it has evidently conquered Dogmatic Theology based on biblical texts and ancient modes of thought, will go hand in hand with Religion … [i.e.] 'a Power in the universe, not ourselves, which makes for righteousness' [quoting without attribution Matthew Arnold, who had actually written of an 'eternal power']." *As science advanced, so would religion: "the love of God and of our neighbor will steadily grow stronger and stronger" throughout the world. After praising Micah and the Epistle of James, White looked forward "above all" to the growing practice of "the precepts and ideals of the blessed Founder of Christianity himself" (vol. 1, p. xii). Ungureanu quotes White that the "most mistaken of all mistaken ideas" is the "conviction that religion and science are enemies" (p. 71). *This echoed both Draper's belief that "true" religion was consistent with science, and T. H. Huxley's 1859 lecture in which he affirmed that the so-called "antagonism of science and religion" was the "most mischievous" of "miserable superstitions." Indeed, Huxley affirmed that, "true science and true religion are twin-sisters" (p. 191). *Chapter 1 locates Draper in his biographical, religious, and intellectual contexts: for example, the common belief in immutable natural laws; the "new" Protestant historiography expressed in the work of such scientists as Charles Lyell and William Whewell; and various species of evolutionism. Comte de Buffon, Jean Baptiste Lamarck, John Herschel, Thomas Dick, Robert Chambers, and Darwin are some of the many writers whose work Draper used. *Chapter 2 examines White's intellectual development including his quest for "pure and undefiled" religion. He studied Merle d'Aubigné's history of the Reformation (White's personal library on the subject ran to thirty thousand items) and German scholars such as Lessing and Schleiermacher who cast doubt on biblical revelation and theological doctrines, in favor of a "true religion" based on "feeling" and an only-human Jesus. As he worked out his history of religion and science, White also absorbed the liberal theologies of William Ellery Channing, Horace Bushnell, Henry Ward Beecher, and Lyman Abbott, among others. *The resulting histories by Draper and White were providential, progressive, and presentist: providential in that God still "governed" (without interfering in) nature and human history; progressive, even teleological, in that faith was being purified while science grew ever closer to Truth; and presentist in that the superior knowledge of the present could judge the inferiority of the past, without considering historical context. *Chapters 3 and 4 situate Draper and White in wider historiographic/polemical Anglo-American contexts, from the sixteenth-century Reformation to the late nineteenth century. Protestant attacks on Roman Catholic moral and theological corruption were adapted to nineteenth-century histories of religion and science, with science as the solvent that cleansed "true religion" of its irrational accretions. Ungureanu reviews other well-known Christian writers, including Edward Hitchcock, Asa Gray, Joseph Le Conte, and Minot Judson Savage, who sought to accommodate their religious beliefs to evolutionary theories and historical-critical approaches to the Bible. *Chapter 5 offers a fascinating portrait of Edward Livingston Youmans--the American editor with prominent publisher D. Appleton and Popular Science Monthly--and his role in promoting the conflict-reconciliation historiography of Draper and White and the scientific naturalism of Huxley, Herbert Spencer, and John Tyndall. *In chapter 6 and "Conclusions," Ungureanu surveys critics of Draper's and White's work, although he neglects some important Roman Catholic responses. He also carefully analyzes the "liberal Protestant" and "progressive" writers who praised and popularized the Draper-White perspectives. Ungureanu is excellent at showing how later writers--atheists, secularists, and freethinkers--not only blurred distinctions between "religion" and "theology" but also appropriated historical conflict narratives as ideological weapons against any form of Christian belief, indeed any form of religion whatsoever. Ultimately, Ungureanu concludes, the conflict-thesis-leading-to-reconciliation narrative failed. The histories of Draper and White were widely, but wrongly, seen as emphatically demonstrating the triumph of science over theology and religious faith, rather than showing the compatibility of science with a refined and redefined Christianity, as was their actual intention. *Draper's History of the Conflict, from the ancients to the moderns, suggested an impressive historical reading program, as did his publication of A History of the Intellectual Development of Europe (rev. ed., 2 vols., 1875 [1863]). But one looks in vain for footnotes and bibliographies to support his controversial claims. White's two-volume study, however, landed with full scholarly apparatus, including copious footnotes documenting his vivid accounts of science conquering theological belief across the centuries. What Ungureanu doesn't discuss is how shoddy White's scholarship could be: he cherrypicked and misread his primary and secondary sources. His citations were not always accurate, and his accounts were sometimes pure fiction. Despite Ungureanu's recovery of German sources behind White's understanding of history and religion, he does not cite Otto Zöckler's Geschichte der Beziehungen zwischen Theologie und Naturwissenschaft (2 vols., 1877-1879), which, as Bernard Ramm noted in The Christian View of Science and Scripture (1954), served as "a corrective" to White's history. *Ungureanu certainly knows, and refers to some of, the primary sources in the large literature of natural theology. I think he underplays the roles of Victorian natural theologies and theologies of nature in reflecting, mediating, criticizing, and rejecting conflict narratives. Ungureanu seems to assume readers' familiarity with the classic warfare historians. He could have provided more flavor and content by reproducing some of Draper's and White's melodramatic and misleading examples of good scientists supposedly conquering bad theologians. (One of my favorite overwrought quotations is from White, vol. 1, p. 70: "Darwin's Origin of Species had come into the theological world like a plough into an ant-hill. Everywhere those thus rudely awakened … swarmed forth angry and confused.") *Ungureanu's is relevant history. Nineteenth-century myth-laden histories of the "warfare between Christianity and science" provide the intellectual framework for influential twenty-first century "scientific" atheists who have built houses on sand, on misunderstandings of the long, complex and continuing relations between faith/practice/theology and the sciences. *This is fine scholarship, dense, detailed, and documented--with thirty-seven pages of endnotes and a select bibliography of fifty pages. It is also well written, with frequent pauses to review arguments and conclusions, and persuasive. Required reading for historians, this work should also interest nonspecialists curious about the complex origins of the infamous conflict thesis, its ideological uses, and the value of the history of religion for historians of science. *Reviewed by Paul Fayter, who taught the history of Victorian science and theology at the University of Toronto and York University, Toronto. He lives in Hamilton, ON.

A l’ère où il semble devenu évident pour beaucoup que l’humanité doive changer sa façon d’habiter la terre, des prédictions d’avenirs très distincts parcourent les réseaux et nos cerveaux. Dans une perspective immédiate de davantage de respect vis-à-vis de la nature, une question pragmatique peut s’ériger en chacun de nous : « que faire ? ». Dans une logique d’écologie de l’humain et de co-énonciation avec le vivant, cet article propose une piste possible vers l’émergence d’une éthique à l’échelle individuelle. Au-delà d’une anxiété paralysante, ou d’une action précipitée, peut-on penser une éthique rassurante, allant de soi ? Après l’examen des causes profondes de la crise écologique, l’idée proposée ici est qu’une co-énonciation avec le vivant, au service du vivant, pour la création d’un nouveau monde écologique, passe à l’échelle individuelle par une harmonie intérieure. Il s’agit alors de sortir de l’emprise des pièges d’un numérique débordant et d’effacer les dissonances internes que nos facettes scientifique et artistique peuvent avoir, dissonances parfois renforcées et/ou révélées par les arts numériques. Nous chercherons à montrer comment, en se réappropriant ces « désaccords intérieurs » et en pratiquant une démarche d’écologie introspective via l’art et la science, nous pouvons progressivement nous « défragmenter » par ce que l’on appellera via un élargissement de concept, une « co-énonciation intra-personnelle ». Par là même, des transformations salutaires pour le collectif humain et non humain s’opèrent. Parallèlement, la mise en place de qualités d’être impliquant le corps et l’esprit pour vivre la co-énonciation ouvre le chemin vers une éthique spontanée, joyeuse, allant de soi. Dans cette optique, les arts numériques deviennent un moyen d’expression créatif parmi d’autres, au service d’une co-énonciation écologique c'est-à-dire respectueuse de la nature, sans en être son substitut.

Au cours des dernières années, l'utilisation d'armes à létalité réduite a augmenté. Ces armes, conçues pour neutraliser des individus présentant un comportement dangereux, peuvent causer des blessures, voire la mort. Des mécanismes de lésions similaires sont observés lors de la déformation arrière des gilets pare-balles au cours d'impact avec projectiles d’arme à feu. Afin de protéger les citoyens et les forces de l’ordre, il est nécessaire de prévenir de tels scénarios. Or aujourd'hui peu d'outils sont disponibles pour aider au dimensionnement de tel équipements. Dans cette optique, ce travail de thèse vise à développer des outils de prédiction du risque de lésion thoracique lors d'impact balistique non pénétrant. Ainsi, un substitut physique de thorax humain et son jumeau numérique sont développés. Dans un premier temps, le modèle numérique HUByx est utilisé comme référence pour construire un modèle numérique simplifié pouvant être fabriqué avec des matériaux disponibles dans le commerce. Les différents matériaux sont caractérisés et leurs lois de comportement sont établies. Une fois validé, ce modèle numérique sert de base pour construire le substitut physique appelé SurHUByx. Celui-ci est équipé de différents capteurs permettant d'enregistrer les données au niveau des côtes et des organes internes lors d'impact. Des cas d'impact précisément décrits dans des rapports sont reproduits sur SurHUByx pour relier les données issues des capteurs à un bilan lésionnel. Enfin, une approche statistique est utilisée pour développer des courbes de probabilité de lésion, permettant d'estimer le risque de lésion suite à un impact sur SurHUByx ou son jumeau numérique SurHUByx FEM
In recent years, the use of less-lethal weapons has increased. These weapons, designed to neutralise individuals exhibiting dangerous behaviour, can cause injuries or even death. Similar injury mechanisms are observed in the rear deformation of bulletproof vests during impacts. To protect citizens and law enforcement personnel, it is necessary to prevent such scenarios. However, today there are few tools available to assist in the sizing of such equipment. In this context, this thesis aims to develop tools for predicting thoracic injury risk during non-penetrating ballistic impacts. Accordingly, a physical substitute of the human thorax and its numerical twin are developed. Initially, the HUByx numerical model is used as a reference to construct a simplified numerical model that can be manufactured using readily available materials. Different materials are characterised, and their material laws are established. Once validated, this numerical model serves as a basis for constructing the physical substitute called SurHUByx. It is equipped with various sensors to record data over the rib and in internal organs during ballistic impacts. Specific impact cases described in case reports are replicated on SurHUByx to correlate sensor data with injury assessments. Finally, a statistical approach is used to develop injury prediction curves, allowing to estimate of the risk of injury following an impact on SurHUByx or its numerical twin, SurHUByx FEM

Le génie tissulaire ossseux est un domaine de la médecine régénératrice qui permet la production de substituts à partir des cellules du patient en association avec des biomatériaux, ou non, et des facteurs de croissance, tels que les bone morphogenetic proteins (BMP). La composition chimique ou l’origine xénogénique de ces biomatériaux peut mener à des échecs de guérison qui se traduisent alors par la non-intégration du greffon au tissu natif environnant ou le rejet par le corps du patient. En outre, en absence de vascularisation, le centre des tissus épais produits se retrouvera avec un apport réduit, voir insuffisant en nutriments et oxygène. Ceci peut diminuer considérablement la survie des greffons et la guérison après la greffe. Nous avons émis l’hypothèse que la prévascularisation de ces substituts osseux procurera un réseau capillaire pouvant favoriser l’ostéogenèse in vitro et la guérison osseuse in vivo. Le but global de cette thèse est de développer un nouveau modèle de feuillet osseux humain prévascularisé produit par la méthode d’auto-assemblage à partir des cellules souches du tissu adipeux (CSTA). Les objectifs sont : 1) Déterminer le potentiel pro-angiogénique de ces feuillets osseux, et étudier le développement de structures microvasculaires bio-imprimées par laser. 2) Caractériser la formation d’un réseau capillaire produit grâce à un ensemencement aléatoire de cellules endothéliales et évaluer l’impact de ce dernier sur l’ostéogenèse, la biominéralisation et la guérison de défauts osseux calvariens. 3) Améliorer l’ostéogenèse des tissus par un traitement à la BMP et déterminer le potentiel de substituts osseux, co-cultivés ou non avec des cellules endothéliales, à stimuler la guérison des défauts osseux alvéolaires. Ainsi, des CSTA ont été induites dans une voie de différenciation ostéogénique pour former des feuillets osseux manipulables. Ces feuillets ont présenté un profil pro-angiogénique avec la sécrétion de molécules, telles que le vascular endothelium growth factor (aussi iv élevé que les feuillets non différenciés) et l’angiopoiétine-1 (2,3 fois plus élevé que les feuillets non différenciés), pouvant favoriser la formation et le maintien d’un réseau capillaire. De larges structures capillaires ont été formées par la bio-impression par laser de cellules endothéliales extraites de cordons ombilicaux humains (HUVEC). L’alignement de ces structures dépend de l’orientation cellulaire des feuillets empilés. Des tissus osseux prévascularisés par la méthode d’ensemencement aléatoire ont permis la formation d’un réseau capillaire 2,1 fois plus dense et 3,7 fois plus ramifié comparativement aux tissus non différenciés. Cependant, la prévascularisation retarde l’ostéogenèse et la biominéralisation in vitro, avec des réductions de la sécrétion en ostéocalcine (1,7 fois) et de la formation d’hydroxyapatite (1,6 fois) dans la matrice des feuillets osseux. Une amélioration de la survie des greffons osseux lorsqu’ils ont été prévascularisés (5,7 fois) a été révélée après 12 semaines d’implantation dans des défauts osseux calvariens créés dans des rats immunodéficents. En outre, les résultats suggèrent que la prévascularisation des tissus osseux ne nuit pas à la cicatrisation osseuse des défauts crâniens. Afin d’améliorer le potentiel du modèle, les effets d’un traitement à la BMP-9 sur l’ostéogenèse des CSTA, ainsi que l’impact de leur co-culture avec des HUVEC durant 21 jours, ont été étudiés. Ainsi, un traitement à la BMP-9 des tissus osseux a permis d’augmenter significativement l’activité de la phosphatase alcaline (3 fois), alors que la prévascularisation permet d’augmenter considérablement l’épaisseur (2 fois) et les propriétés mécaniques (pourcentage de déformation : 1,6 fois, module de Young : 3,6 fois et résistance à la traction : 3,7 fois) des tissus osseux après 21 jours de co-culture. Des tissus osseux et stromaux non traités, prévascularisés ou traités à la BMP-9 ont été greffés pendant dix semaines dans des défauts osseux alvéolaires créées chez des rats immunodéficients suite à des extractions dentaires. Un biomatériau chirurgical de comblement osseux a été utilisé comme contrôle positif. Des analyses par microtomodensitométrie et des observations histologiques ont révélé une guérison osseuse élevée lorsque les défauts ont été greffés avec des tissus osseux traités à la BMP-9 ou non. En v outre, ces défauts ont présenté un volume osseux similaire à ceux comblés avec le biomatériau. Finalement, ce nouveau modèle de tissu osseux humain prévascularisé pourrait ultimement offrir aux cliniciens une solution avantageuse pour les traitements de petits défauts osseux en plus de représenter, pour les chercheurs fondamentaux, un outil de recherche in vitro performant.
Bone tissue engineering is a field of regenerative medicine that allows the production of substitutes from the patient’s cells in association with either biomaterials and/or growth factors, such as bone morphogenetic proteins (BMPs). The chemical composition or the xenogeneic origin of these biomaterials can lead to healing failures that would result in the non-integration of the graft to the surrounding native tissue or the rejection by the patient’s body. Moreover, in the absence of vascularization, the center of thick tissues produced will end up with reduced or insufficient intake of nutrients and oxygen. This can significantly reduce graft survival and post-implantation healing. We hypothesized that the prevascularization of these osseous substitutes will provide a capillary network that can promote in vitro osteogenesis and in vivo bone healing. The overall goal of this thesis is to develop a new model of a prevascularized human osseous cell sheet produced by the self-assembly method using human adipose-derived stem cells (hASCs). The aims are: 1) Determine the pro-angiogenic potential of these osseous cell sheets, and study the development of laser-assisted bioprinted microvascular structures. 2) Characterize the formation of a capillary network produced by random seeding of endothelial cells and evaluate its impact on osteogenesis, biomineralization, and the healing of calvarial bone defects. 3) Improve osteogenesis of the tissues using bone morphogenetic protein (BMP) treatment and determine the potential of osseous substitutes, co-cultured or not with endothelial cells, to heal alveolar bone defects. Thus, hASCs have been induced towards an osteogenic differentiation pathway to form manipulable osseous cell sheets. These cell sheets showed a pro-angiogenic profile with the secretion of molecules, such as vascular endothelium growth factor (as high as non-induced cell sheets) and angiopoietin-1 (2.3-fold higher than non-induced cell sheets), that can vii promote the formation and the maintenance of a capillary network. Large endothelial structures were formed by laser-assisted bioprinting of human umbilical vein endothelial cells (HUVECs). The alignment of these structures depends on the cellular orientation of the stacked cell sheets. Prevascularized osseous tissues, which were vascularized by the random seeding method, allowed the formation of a capillary network 2.1-fold denser and 3.7-fold more connected compared to non-induced tissues. However, prevascularization delayed osteogenesis and biomineralization in vitro, with decreases in osteocalcin secretion (1.7-fold) and hydroxyapatite formation (1.6-fold) in the matrix. Prevascularization of the osseous grafts revealed an improvement of their survival (5.7-fold) after 12 weeks of implantation in calvarial bone defects created in immunodeficient rats. In addition, these results suggest that the prevascularization of osseous tissue does not interfere with the healing of cranial bone defects. To improve the potential of the model, the osteogenic effect of BMP-9 treatment on hASCs, as well as the impact of their co-culture with HUVECs for 21 days, were investigated. BMP-9 treatment of osseous tissues significantly increased the activity of alkaline phosphatase (3-fold), while prevascularization significantly increased the thickness (2-fold) and the mechanical properties (percent deformation: 1.6-fold, Young modulus: 3.6-fold and tensile strength: 3.7-fold) of the osseous tissues after 21 days of co-culture. Untreated, prevascularized or BMP-9-treated osseous and stromal tissues were grafted for 10 weeks into alveolar bone defects created in immunodeficient rats following tooth extractions. A surgical bone filler biomaterial was used as a positive control. Micro-computed tomography scans and histologic observations revealed elevated bone healing when the defects are grafted with BMP-9-treated or non-BMP-treated osseous tissues. In addition, these defects exhibited a similar bone volume fraction at the implantation site after 10 weeks compared to those filled with the biomaterial. viii Finally, this new model of prevascularized human osseous tissue could ultimately offer clinicians an advantageous solution for the treatment of small bone defects and represent, for fundamental researchers, a powerful in vitro research tool.

La recherche en biomécanique des chocs est une nécessité pour améliorer la sécurité dans les transports. Pour une meilleure évaluation des critères lésionnels lors des simulations de crash, le manque de représentativité des modèles EF du thorax humain pourrait être comblé par une démarche de personnalisation aussi bien au niveau géométrique que mécanique. Cette thèse se base sur l'étude de 18 sujets humains post-mortem. A partir des données d'imagerie, les différentes dimensions des côtes sont analysées. La corrélation de ces paramètres aboutit à la prédiction de 192 dimensions à partir d'un unique paramètre d'entrée. A une échelle inférieure, un protocole innovant a permis de coupler des informations microstructurales issues d'un μCT avec la forme extérieure des côtes. 2 hémi-thorax ont été micro-scannés afin de générer une cartographie complète des épaisseurs d'os cortical. Une stratégie a été mise en place pour proposer un algorithme prédisant l'intégralité de cette géométrie locale d'après un seul tronçon de côte. La pertinence de cette personnalisation a été évaluée par une étude de sensibilité sur des modèles EF. Les résultats d'essais de traction sur os cortical montrent un comportement différent entre les éprouvettes prélevées sur la table interne ou externe des côtes. Une caractérisation précise de la structure interne de l'os cortical, couplé à des essais de micro-traction in-situ, a pu apporter des éléments de réponse sur cette différence. Unalgorithme de personnalisation a été aussi proposé pour les propriétés mécaniques, complétant ainsi la démarche d'adapter les modèles EF du thorax à chaque individu afin d'améliorer leur biofidélité.

Quatorze microporcs de l'espèce YUCATAN furent opérés de vitrectomie suivie par l'injection de gel de collagène de type quatre, d'origine placentaire humaine, en tant que substitut du vitré. Les yeux gauches furent opérés, les yeux droits servant de témoins. Un suivi fut réalisé chez onze microporcs sur une période : variant de quinze jours à six mois avec études, sous anesthésie générale, clinique, tonométrique, E. R. G. Et histologique. Les trois derniers microporcs servirent à l'étude de la durée de suivie du collagène intra-oculaire. Le gel de collagène humain est apparu dans l'ensemble bien toléré (pas de toxicité rétinienne) mais son élimination a été rapide (environ quinze jours).

La respiration est un phénomène vital qui implique une synergie entre diverses structures anatomiques qui constituent le thorax. La physiologie articulaire reste un parent pauvre de la physiologie et la littérature concernant la quantification de la cinématique 3D des articulations du thorax durant le mouvement respiratoire est rare. Ce travail se concentre sur le développement et l'application d'une méthodologie permettant de répondre à cet objectif. La méthode développée combine le traitement de données tomodensitométriques réalisées à trois volumes pulmonaires différents et des techniques d'infographies. Les amplitudes (ROMs) et axes de mouvements (axe hélicoïdaux moyen, AHMs) ont été obtenus au niveau des articulations costo-vertébrales de 12 sujets asymptomatiques. En résumé, les amplitudes diminuent graduellement dans les étages inférieurs ; le volume pulmonaire et l'étage costal influencent significativement les amplitudes costales ; l'orientation des AHMs ne diffère pas entre les étages costaux. En complément, la méthode a été appliquée pour un échantillon de 10 patients atteints de mucoviscidose. La condition pathologique influençait significativement les amplitudes de mouvements mais pas l'orientation des AHMs. Enfin, le déplacement sternal, les variations de l'angle sternal et la cinématique des articulations sternocostales a été analysée. Les déplacements angulaires des côtes par rapport au sternum diminuaient dans les étages inférieurs comme au niveau des articulations costo-vertébrales. L'orientation des AHMs des articulations sternocostales ne différait pas entre les étages. Une corrélation linéaire a été mise en évidence entre les déplacements verticaux du sternum et les amplitudes de mouvement costales au niveau costo-vertébral et sternocostal. Ce travail contribue de façon substantielle à la modélisation 3D du thorax humain durant le mouvement respiratoire d'un point de vue qualitatif et quantitatif
Breathing is a vital phenomenon that implies synergy of various anatomical structures that constitute the thorax. Joint physiology remains a relatively poorly-known component of the overall thorax physiology. Quantitative literature related to in vivo thorax kinematics during breathing is scarce. The present work focuses specifically on developing and applying a methodology to reach this goal. The developed method combined processing of CT data obtained at different lung volumes and infographic techniques. Detailed ranges of motion (ROMs) and axes of movement (mean helical axes, MHAs) were obtained at costovertebral joints in 12 asymptomatic subjects; rib ROMs gradually decrease with increasing rib number; lung volume and rib level have a significant influence on rib ROM; MHAs did not differ between rib levels. In addition, the method was applied on a sample of 10 patients with cystic fibrosis. The pathological condition significantly influenced CVJ ROMs while the orientation of the MHAs did not differ. Finally, the sternal displacement, sternal angle variations and sternocostal joints (SCJ at rib1 to 7) kinematics during breathing motion were analyzed. Rib ranges of motion relative to sternum decreased with increasing rib number similarly to CVJ. Orientation of the MHAs did not differ between SCJ levels. A significant linear correlation was demonstrated between sternum vertical displacement and rib ranges of motion at both CVJ and SCJ. The present work substantially contributes to 3D modelling of human thorax in breathing at a joint level both qualitatively and quantitatively

Lorsque des vaisseaux autologues ne sont pas disponibles pour faire un pontage, des greffons synthétiques sont utilisés mais avec des taux d’échec élevés. En effet, malgré leurs bonnes propriétés mécaniques, la surface synthétique de ces greffons entraîne de la thrombose et de l’hyperplasie intimale ayant pour conséquence une mauvaise perméabilité du substitut à long terme pour de nombreuses applications. Par ingénierie tissulaire, des greffons vasculaires entièrement biologiques et humains ont déjà été produits par roulage de feuillets de matrice extracellulaire synthétisée par des fibroblastes dermiques humains in vitro. Grâce à une nouvelle méthode d’assemblage basée sur une approche textile, des greffons ont été produits trois fois plus rapidement. Pour ce faire, le feuillet a été découpé en fils afin de permettre la construction d’un substitut vasculaire par tissage. Cette thèse comporte trois articles. Le premier visait à montrer la composition riche de la matrice, décrire l’organisation de son réseau complexe de collagènes et démontrer que la dévitalisation par séchage de la matrice n’a pas affecté significativement cette organisation. Le deuxième avait pour but de décrire les propriétés mécaniques des fils en fonction du torsadage et/ou de l’âge de la matrice ainsi que l’effet sur la force de différents traitements nécessaires au processus de fabrication. Les différentes applications de l’approche textile dans la construction de structures complexes ainsi que les propriétés mécaniques des substituts tissés ont également été évaluées. Le troisième article a montré la faible réponse inflammatoire ainsi que le potentiel d’intégration et de remodelage de la matrice in vivo. Par ailleurs, la décellularisation n’a pas montré de résultats supérieurs à la dévitalisation, permettant ainsi de s’affranchir d’une étape de fabrication supplémentaire et potentiellement délétère à l’organisation biologique de cette matrice. En conclusion, cette thèse constitue la première démonstration de la fabrication de textiles humains mécaniquement très forts mais sans utilisation de matériel exogène. La dévitalisation couplée à l’approche textile ont permis de créer un modèle allogénique plus simple, plus rapide et moins coûteux mais avec un potentiel d’intégration in vivo intact. Ce modèle sera très prochainement étudié par implantation à long terme dans la circulation sanguine
When autologous blood vessels are not available for bypass surgery, synthetic grafts are used but display high failure rates. Indeed, despite their good mechanical properties, their synthetic surface lead to thrombosis and intimal hyperplasia, which cause poor long-term patency in many applications. Using tissue engineering, completely biological and human vascular grafts have been produced by rolling sheets of extracellular matrix synthesized by dermal human fibroblasts in vitro. Using a new assembly technique based on a textile approach, grafts were produced three-time faster. To do so, sheets were cut into yarns to construct vascular substitute by weaving. This manuscript includes three articles. The first one aimed at showing the rich composition of the matrix, describing the organization of its complex network of collagens and demonstrating that the devitalization by drying the matrix did not significantly affect this organization. The second one described the mechanical properties of the yarns depending on the twisting, matrix age or different treatments useful for the manufacturing process. It also demonstrated some of the assembly techniques possible with this human yarn, as well as its possible use as a suture or to build a vascular graft. The third article showed the survival of the yarns subcutaneously implanted for 6 month in nude rats. The implants created little inflammatory response, were mildly remodeled and kept a significant mechanical strength. Decellularization did not show results improvement compared to the simple devitalization, demonstrating that the remaining cellular fragments were not a meaningful activator of the innate immune system. To conclude, this thesis is the first demonstration of the production of human textiles, without using any exogenous material and that are mechanically very strong. Both the devitalization and the textile approach have allowed to create a simpler allogeneic model, faster and cheaper but with an intact potential of integration in vivo, that will be studied very soon with a long-term implantation of the textile in the bloodstream

Cette étude fait partie du domaine de la sécurité secondaire dont le but est de diminuer les conséquences d'un accident routier sur les usagers du véhicule. Cette recherche est une contribution à l'analyse de l'influence des facteurs extérieurs provoquant les lésions sur le mécanisme et la gravité des blessures et à l'estimation de la tolérance du thorax humain lorsqu'il est heurté transversalement dans les conditions similaires à un choc latéral automobile. Dans ces travaux, nous donnons les équations de prédiction du risque de blessure thoracique, en utilisant les résultats d'essais sur cadavres humains au choc latéral. Nous analysons également le mécanisme de blessure par une description mathématique simplifiée des réponses mécaniques. Un nouveau critère de blessure est proposé. Un modèle mathématique paroi/thorax est développé, permettant d'évaluer les influences de la vitesse d'impact et de la rigidité de la surface d'impact. Enfin, nous déterminons des valeurs seuils des réponses mécaniques du mannequin EUROSID, qui correspondent à un certain niveau de risque de blessure
The aim of this research is to diminish the consequences of road accidents for those involved. An analysis is carried out of the external factors influencing the gravity and mechanisms of injury. The tolerance of the human thorax in lateral impact is also estimated with conditions similar to a side impact motor accident

Breathing is a vital phenomenon that implies synergy of various anatomical structures that constitute the thorax. Joint physiology remains a relatively poorly-known component of the overall thorax physiology. Quantitative literature related to in vivo thorax kinematics during breathing is scarce. The present work focuses specifically on developing and applying a methodology to reach this goal. The developed method combined processing of CT data obtained at different lung volumes and infographic techniques. Detailed ranges of motion (ROMs) and axes of movement (mean helical axes, MHAs) were obtained at costovertebral joints in 12 asymptomatic subjects; rib ROMs gradually decrease with increasing rib number; lung volume and rib level have a significant influence on rib ROM; MHAs did not differ between rib levels. In addition, the method was applied on a sample of 10 patients with cystic fibrosis. The pathological condition significantly influenced CVJ ROMs while the orientation of the MHAs did not differ. Finally, the sternal displacement, sternal angle variations and sternocostal joints (SCJ at rib1 to 7) kinematics during breathing motion were analyzed. Rib ranges of motion relative to sternum decreased with increasing rib number similarly to CVJ. Orientation of the MHAs did not differ between SCJ levels. A significant linear correlation was demonstrated between sternum vertical displacement and rib ranges of motion at both CVJ and SCJ. The present work substantially contributes to 3D modelling of human thorax in breathing at a joint level both qualitatively and quantitatively.
Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished

L'électroporation est une méthode physique utilisant le champ électrique pour perméabiliser transitoirement la membrane plasmique afin de faciliter l'entrée de molécules d'intérêt thérapeutique dans les tissus ciblés. La principale application clinique est l'électrochimiothérapie (ECT), un traitement anticancéreux local utilisé pour traiter les tumeurs primaires et métastases. La seconde application est l'électrotransfert de gène (EGT), une méthode pour introduire des acides nucléiques à l'intérieur des cellules. Enfin, l'électroporation irréversible (IRE) est une méthode utilisée pour tuer les cellules grâce à la perméabilisation permanente des membranes plasmiques. Même si les mécanismes in vitro sont de mieux en mieux compris, l'efficacité in vivo est variable selon le tissu cible. En effet, bien que l'électrotransfert d'ADN soit très efficace in vitro sur des cultures en deux dimensions (2D), il est souvent beaucoup moins efficace in vivo, ce qui limite ses applications cliniques. L'organisation du tissu in vivo est plus complexe que la culture cellulaire in vitro car les cellules développent des jonctions intercellulaires et une matrice extracellulaire (MEC). Des études in vivo ont démontré que la composition de la MEC module la biodistribution de l'ADN dans le tissu et donc l'efficacité de l'électrotransfert de gène. La réponse de la MEC à l'application de champ électrique dans ce processus reste encore à définir afin d'améliorer l'efficacité de cette méthode. Les modèles classiques en 2D ne possèdent pas cette organisation architecturale tridimensionnelle (3D) leur permettant d'être physiologiquement comparable au tissu natif. Afin d'étudier les mécanismes d'électrotransfert d'ADN à l'échelle des tissus, nous avons utilisé un modèle de peau humaine 3D pour imiter et prédire les situations in vivo. Les objectifs de ce travail étaient d'étudier le rôle et la réponse de la MEC cutanée lors de l'électrotransfert de gène à l'échelle du tissu. La première partie de ce projet a été de caractériser la MEC du substitut dermique reconstruit par ingénierie tissulaire. La MEC a été caractérisée par microscopie électronique, coloration histologique et génération de seconde harmonique (SHG). Pour évaluer si ce modèle imite efficacement la réponse in vivo observée lors de l'électroporation, une gamme de voltage utilisant des paramètres électriques ECT ou EGT a été appliquée et la perméabilisation cellulaire ainsi que l'expression du plasmide ont été analysées sur tissu frais. Dans la deuxième partie, nous avons étudié les effets directs et indirects du champ électrique pulsé sur les collagènes fibrillaires.[...]
Electroporation is a physical technique using external electric field application to efficiently deliver therapeutic molecules of interest in targeted tissues. Its principle is based on a transient permeabilization of the plasma membrane, which facilitates the entry of molecules inside the cell. The main clinical application is electrochemotherapy (ECT), a local cancer treatment already used for treatment of primary tumors and metastases. The second medical application of electroporation is gene electrotransfer (GET), which is a method to introduce plasmids inside cells. Electroporation is also a method used to kill cells, through permanent plasma membrane permeabilization, called irreversible electroporation (IRE). Even if the in vitro mechanisms are more and more understood, in vivo effectiveness remains partial, depending on the targeted tissue type. Indeed, although DNA electrotransfer is highly effective for gene delivery on 2D cell culture in vitro, it is often much less efficient in vivo, which leads to a limited use for clinical applications. In vivo tissue organization is more complex than cell culture in vitro since cells develop intercellular junctions and produce extracellular matrix (ECM). The ECM composition was shown in vivo to modulate gene electrotransfer efficiency, so it seems to play a role in the mechanisms governing the biodistribution of DNA in a complex environment. Very little is known about ECM role and response to electric field application in this process. A better understanding of the effects of the electric field on the ECM would improve the efficiency of this method. Classical 2D models used for the study of electroporation do not exhibit this three-dimensional (3D) architectural organization allowing them to be physiologically comparable to native tissue. In order to study DNA electrotransfer mechanisms at tissue scale, we integrate the use of human 3D skin model that helps to mimic and predict in vivo situation. The objectives of this work were to investigate the role and response of cutaneous ECM during gene electrotransfer at tissue scale. The first part of this project was to characterize the ECM content of a 3D reconstructed human dermal substitute produced by tissue engineering. ECM was characterized in this tissue by electron microscopy, histology staining and generation of second harmonic (SHG). To assess if this model can efficiently mimic the in vivo response observed during electroporation, a range voltage using ECT or GET electrical parameters were apply and cell permeabilization as well as plasmid expression were analyzed on fresh tissue by two-photon microscopy. In the second part, we studied direct and indirect effects of pulsed electric field on the fibrillary collagens.[...]

This chapter concentrates on the mimetic theory of Rene Girard in evaluating foundational myths of violence. It shows Girard's notion of the scapegoating mechanism, whereby a substitute victim absorbs the mimetic animosities of the entire group and thereby promotes peace, as applicable to the disturbing tendency to direct violence outward toward exogenous groups. According to Girard, competition is the main source of human violence. His explanation, that violence has its roots in competition or mimetic rivalry, contributes to Thomas Hobbes, who also highlighted this cause of violence at the beginning of the modern era. The Abrahamic solidarity with the victim easily becomes an aggressive weapon if taking the side of the victim is not connected with the forgiveness of persecutors. Girard interprets the imitation of Christ in the context of rivalries prohibited in the tenth commandment of the First Testament.

The German mathematician Gottfried Wilhelm Leibniz (1646–1716) is perhaps best remembered in science as the co-inventor (with Newton) of the differential calculus. In our story, however, he has a presence not so much because, like his great French contemporary the philosopher Blaise Pascal (1623–1662), he built a calculating machine—in Pascal’s case, the machine could add and subtract, whereas Leibniz’s machine also performed multiplication and division—but for something he wrote vis-à-vis calculating machines. He wished that astronomers could devote their time strictly to astronomical matters and leave the drudgery of computation to machines, if such machines were available. Let us call this Leibniz’s theme, and the story I will tell here is a history of human creativity built around this theme. The goal of computer science, long before it came to be called by this name, was to delegate the mental labor of computation to the machine. Leibniz died well before the beginning of the Industrial Revolution, circa 1760s, when the cult and cultivation of the machine would transform societies, economies, and mentalities. The pivot of this remarkable historical event was steam power. Although the use of steam to move machines automatically began with the English ironmonger and artisan Thomas Newcomen (1663–1727) and his invention of the atmospheric steam engine in 1712, just 4 years before Leibniz’s passing, the steam engine as an efficient source of mechanical power, as an efficient means of automating machinery, as a substitute for human, animal, and water power properly came into being with the invention of the separate condenser in 1765 by Scottish instrument maker, engineer, and entrepreneur James Watt (1738–1819)—a mechanism that greatly improved the efficiency of Newcomen’s engine. The steam engine became, so to speak, the alpha and omega of machine power. It was the prime mover of ancient Greek thought materialized. And Leibniz’s theme conjoined with the steam engine gave rise, in the minds of some 19th-century thinkers, to a desire to automate calculation or computation and to free humans of this mentally tedious labor.